Lung transplantation (LTX) reduces morbidity and mortality from respiratory failure, but acute and long-term outcomes remain poor. Primary lung graft failure occurs in up to 20% of recipients, and by 5 years, over half of all patients develop bronchiolitis obliterans (BO), the major cause of death outside of infections. This project focuses on the balance between two countervailing eicosanoid pathways of cellular injury and repair in the lungs, prostaglandins (PGs) and leukotrienes (LTs), in acute and chronic lung injury associated with transplantation. Preliminary data show PGE^ added to the lung flush/preservation solution reduces ischemia/reperfusion (I/R) injury (a known contributor to BO), by stimulating the cAMP-dependent protein kinase. Using an air-flow permissive airway transplant model that we developed, mice deficient in the 5- lipoxygenase (5-LO) gene, responsible for the initial step in LT synthesis, appear to be protected from BO. In vitro supporting data suggest that in lung-derived myofibroblasts, LTs promote but PGs suppress inflammatory mediator synthesis and fibrosis. We hypothesize that eicosanoids modulate both the acute and chronic host responses to LTX injury, with PGs preserving vascular homeostasis and limiting airway obliteration but LTs having the opposite effect. The Specific Aims are to determine the role of (1) endogenous PGs and (2) LTs and their synthetic enzymes and signaling receptors in the response of the lungs to ischemic/transplantation injury, using rodent models of lung I/R, LTX, and airway transplantation. Aim (3) will determine the role of eicosanoid balance in BO development following second hit (ischemic, viral) injury, use genetic (COX, prostanoid receptor [EP2], and 5-LO deficient) and pharmacologic (COX and 5-LO inhibitor, LT receptor antagonist) strategies. Inhalation of PGs will be studied as a potential new therapeutic strategy to reduce primary graft failure and BO. Taken together, these experiments will elucidate the role of the prevailing eicosanoid balance as a critical facet of the host response to LTX. Public Health Implications: Certain native substances made by cells in the lungs can injure blood vessels and airways in transplanted lungs, leading to their obstruction, whereas other related substances are protective. This grant seeks to understand the balance between these injurious and protective substances, to develop strategies which may tip the balance in favor of protecting transplanted lungs from lethal injury.